Draft Presentation

Biosimilars & BioBetters— The Differences Between

Both and the Two Very Different FDA Regulatory Pathways

Jennifer L DiGiacinto, PharmD

February 7, 2017 Harvard Law School

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Overview

• Biosimilars & BioBetters Definitions • Current State of Biosimilars • Concept of BioBetters • Differences between Biosimilars and BioBetters

Development • Regulatory Pathways for Biosimilars & BioBetters • Cost and Development Time • FDA Guidance

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Definition Biosimilar • Biosimilars-are products that are “highly similar” to the biologic reference

product(s) regarding quality, biological activity, safety, and efficacy. – The Biologics Price Competition and Innovation Act of 2009 (BCPI Act)

signed into law March 23, 2010 BPCI Act creates an abbreviated licensure pathway for biological

products shown to be “highly similar” to and/or “interchangeable” to an FDA licensed reference product

– Biosimilars are not generics – due to complex nature and produced in living systems it can never duplicate the originator do not follow the same regulatory pathway as a generic 351(k) vs.

505(j) (generic / ANDA) – Perceived to be a lower business risk vs original biologic – Follows stringent legal and regulatory pathways across the globe – No exclusivity granted for “highly similar” status / 1 year Exclusivity

granted for “interchangeability” status – Approval across all indications for the Reference Biologic is possible – Must wait for the Innovator’s patent to expire prior to submitting to FDA

for approval

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Definition-Biobetter

• BioBetter-is a biological that has been structurally and/or functionally altered to achieve an improved or different clinical performance (eg, altered structure, compared to an already approved biologic product)

Chemical modification (PEGylation, Glycosylation), New Formulation (novel ROA, modified released)

Longer half-life, less immunogenic, better efficacy, better safety, less frequent dosing, better purity, longer shelf-life, etc.

– Term “biobetter” surfaced in context to Biologics Price Competition and Innovation Act (BCPI Act 2010-”Biosimilars Act”)

– Given the stringent regulatory requirements of highly similar and interchangeability required for a biosimilar, Sponsors turned their interest to biobetters.

– 351(a) –BLA same as the originator regulatory pathway – Perceived to be a lower business risk vs original biologic – Exclusivity (eg, 12 years) and Patentable

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Current State of Biosimilars • US Biosimilars (2010) start was sluggish due to the stringent pathway

and; whereas, Europe had much more traction earlier on (2005) – To date, 4 biosimilars (filgrastim (2015), infliximab (April 2016), etanercept

(August 2016) and adalimumab (September 2016) have been approved by FDA (“as highly similar” but not “interchangeable”; whereas, Europe currently has 20 biosimilar products approved (since 2005). Biosimilar which is approved as “highly similar” to reference product and

shown to have no meaningful clinical differences Interchangeable Biosimilar-in addition to meeting the biosimilarity, is expected

to produce the same clinical result as the reference product in any given patient

Highly similar = “B” rating vs “I” rating for “interchangeable” in the Purple Book

• Early on major hurdle to US biosimilars is no real pathway or clarity of how to obtain “interchangeable” status—consider to be the golden egg-which requires a higher bar of evidence, more studies and was not clearly defined how to obtain by FDA. – US clinicians expressed concerns on how to determine if a product will be

interchangeable Proprietary and Confidential 5

Current State of Biosimilars, Continued

• FDA just released a new draft Guidance for Industry-- Interchangeable Biosimilar Products-

• An interchangeable product is expected

to produce the same clinical result as the reference product in any given patient.

• Sponsor must demonstrate if the product is administered more than once to an individual, the safety and efficacy risks of alternating or switching between the use of the biosimilar product and the reference product is not greater than the risk of using only the reference product.

• FDA expects clinical data to demonstrate this in all of the reference product’s licensed conditions of use

• “Switching Studies”-outlined in guidance

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Current State of Biosimilars, Continued

– US current Biosimilar market is finally coming to existence and signs of future potential; however, still some uncertainties:

– Key issues and drivers: More originator biologics coming off patents=more opportunity

for biosimilars o 2009-2019 $50B of the market value of biologics will come off

patent o 100B of the market value of biologics will come off patent by 2020

US pricing will play a role in biosimilars success Solidifying the policy and regulatory environment that will

expedite the development Education to the clinicians, patients, payers, and policy makers

as to the safety and efficacy of biosimilars

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Concept of BioBetter

– 2007 “BioBetter” coined by CEO (G.V. Prasad) of Dr.

Reddy’s Laboratories at a bioinvestor’s conference – Not actually a new concept

Pegylation of existing molecules is well-known method for extending the half-life of a biologic molecule

Results into a reduced dosing schedule for the patient (improvement of QOL)

First pegylatyed version of the interferon alfa (Pegasys®) was approved by EMA in 2002, but wasn’t until 2007 the term “biobetter” was coined.

– BioBetter –development most important element is defining “better than” vs. a Biosimilar trying to achieve highly similar and/or interchangeable is the most important development goal

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Concept of BioBetter, Continued

– Biobetter refers to a recombinant protein drug which is in the same class as an existing original biologic (Innovator) but is not identical and has a different active compound when compared to the Innovator It is improved or an upgraded version of the innovator with no

structural limitations and may include molecular/chemical modifications

– Biobetter aims for the same target as the innovator, but has a longer activity duration and usually at lower doses with fewer adverse effects

– Biobetters are like new drugs and must be developed like a new BLA- well-defined pathway

– Biobetters do not have to wait until a patent expires for the Innovator; may obtain a patent or data exclusivity (up to 12 years) based on their innovative properties, and will command a premium price Can only be marketed for the approved indication

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Differences between Biosimilars and BioBetters Development

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H Gorham, The Value of BioBetters, 2016

Regulatory Pathways for Biosimilar

Biosimilar Regulatory Pathway 351(k)

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E. Olech 2016

Regulatory Pathways for Biosimilar

• Under the BCPI Act- – The FDA interpretation is a biologic is first approved as a biosimilar that is

“highly similar” to the Reference product and may (or may not) then be determined to be “interchangeable” to the Reference product Approvals are made on a “case by case” decision looking at the “totality” of the

package – NEW FDA Guidance to Industry: Demonstrating Interchangeability with a

Reference Product (Jan 2017):

– D

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Regulatory Pathways for BioBetters

• 351(a)-Traditional BLA – Longer and more

expensive clinical trials – must follow new-drug approval pathway

• How much better? – Must be significantly better

to gain acceptance over established reference product or biosimilars thereof. Large clinical trials likely needed to prove clinical superiority over reference product

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Costs and Development Time

• Innovator Biologic: BLA – 10-15 years to develop – R&D Costs: $1.3-$2.6B /Failures into account $5B

• Biosimilar: • 8-10 years to develop • $100-$200M

– Celltrion invested $112M of Remsima, a biosimilar to Remicade

• Monoclonal antibody biosimilar (Mab) >> $250M

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FDA Guidance for Biosimilars

• 8 FDA Guidances to Industry for Biosimilars – Focus on therapeutic protein products – Discusses general scientific principles – Outlines a stepwise approach to generating data and the

evaluation of residual uncertainty at each step – Introduces the “totality-of-the-evidence” approach

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm

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FDA Guidance for Biosimilars • Biosimilar Initial Advisory Meeting

– General discussion regarding feasibility of licensure of particular product under PHS Act

• BPD Type 1 Meeting – Dispute resolution, clinical holds, SPA, important safety issue – Type 1 Meetings should be scheduled within 30 days of the date of the written

request • BPD Type 2 Meeting

– Specific Issue: study design/endpoints and can involve review of substantive data

• BPD Type 3 Meeting – In-depth data review and advice meeting-extensive data package

Analytical similarity data / future proposed clinical trials • BPD Type 4 Meeting

– Discuss the format and content of Biosimilar biological product application

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Outlined in FDA Guidance to Industry: Formal Meetings Between the FDA and Biosimilar Biological Sponsors or Applicants

FDA Guidance for BioBetters

• Meetings and guidance would follow standard practice for new BLAs – Type A Meetings- a meeting requested to help an

otherwise stalled product development program to proceed Dispute resolution, clinical holds, SPA Type A Meetings should be scheduled within 30 days of the

date of the written request – Type B Meetings—

PIND, EOP1, EOP2, Pre-Phase3, Pre-BLA o Occur within 60 days of FDA written receipt of a meeting

request

– Type C Meetings Any other meeting that does not fall under Type A or Type B

o Occurs 75 days of FDA receipt of written request

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Outlined in FDA Guidance to Industry: Formal Meetings Between the FDA and Sponsors or Applicants

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Backup Slides

Biosimilars vs BioBetters

• Biotechnology Information Institute reports: – 21 Biosimilars and 12 Biobetters for Herceptin currently

companies are woraing on – 21 Biosimilars and 13 Biobetters for Rituxan

• A new Biosimilar will enjoy a large market for a short period of time—until next new Biosimilar approved or BioBetter is approved

• A new “highly similar” Biosimilar does not receive the 180 day exclusivity period a ANDA product receives upon approval (Hatch-Waxman Act)

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Biosimilars vs BioBetters

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Table from Bill Stohl, Janssen, IBC Biopharm Prod Week, 29 Feb 2012, SD, CA